Recent advances in amyotrophic lateral sclerosis research: perspectives for personalized clinical application

Abstract

Treatment of amyotrophic lateral sclerosis (ALS) has been fueled, in part, by frustration over the shortcomings of the symptomatic drugs available, since these do not impede the progression of this disease. Currently, over 150 different potential therapeutic agents or strategies have been tested in preclinical models of ALS. Unfortunately, therapeutic modifiers of murine ALS have failed to be successfully translated into strategies for patients, probably because of differences in pharmacokinetics of the therapeutic agents, route of delivery, inefficiency of the agents to affect the distinct pathologies of the disease or inherent limitations of the available animal models. Given the multiplicity of the pathological mechanisms implicated in ALS, new therapies should consider the simultaneous manipulation of multiple targets. Additionally, a better management of ALS therapy should include understanding the interactions between potential risk factors, biomarkers and heterogeneous clinical features of the patients, aiming to manage their adverse events or personalize the safety profile of these agents. This review will discuss novel pharmacological approaches concerning adjusted therapy for ALS patients: iron-binding brain permeable multimodal compounds, genetic manipulation and cell-based treatment.

Fig. 1

Chemical structure of the novel brain permeable, multifunctional iron chelating compounds and the natural iron chelator, EGCG. a M30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline) and HLA20 (5-[4-propargylpiperazin-1-ylmethyl]-8-hydroxyquinoline), restrained the propargyl moiety. b The major polyphenolic compound of green tea, (−)-epigallocatechin-3-gallate, EGCG

Fig. 2

Neuroprotective targets involved in mechanism of action of the multifunctional iron chelating compounds (e.g. M30, HLA20). Full explanation is discussed in the text. Abbreviations; brain derived neurotrophic factor (BDNF); erythropoietin (EPO); extracellular signal-regulated kinase (ERK); hypoxia-inducible factor (HIF); glucose transporter 1 (GLUT-1); glycogen synthase kinase 3 (GSK-3)β; PI3K, phosphatidylinositol 3-kinase protein kinase C (PKC); transferrin receptor (TfR); tyrosine hydroxylase (TH); vascular endothelial growth factor (VEGF)

Fig. 3

Attenuation of the neuritogenic effect of M30 and HLA20 by specific inhibitors of PKC and MAPK/ERK kinase (MEK). NSC-34 cells were incubated with PKC inhibitor GF109203X (2.5 µM) or MEK inhibitor PD98059 (10 µM) for 1 h before administration of M30 (10 µM) or HLA20 (10 µM) for a further 24 h. The cells were fixed and permeabilized for GAP-43 detection. a The images are representative fields from three independent experiments. b the histogram represents averages of the differentiated cell percentages (± SEM). One-way ANOVA followed by Student’s t-test was used for statistic analysis. * p < 0.001 vs. respective controls; # p < 0.001 vs. M30 and HLA20 only (without inhibitors) treated cells. (Reproduced from [36])

Fig. 4

Effect of M30 treatment on motor dysfunction onset, survival time, motor deficits and weight in G93A-SOD1 mutant ALS transgenic mice. Mutant G93A-SOD1 mice were treated by the oral gavage method with vehicle (control) or M30 (1 mg/kg) four times a week starting from the 70th day after birth and continuing until death. Plots present cumulative probability of a the symptoms onset (n = 13–16 per group; p < 0.001; log -rank Mantel-Cox test) and b overall survival (n = 13–16 per group; p < 0.025; log -rank Mantel-Cox test) against the age of the mutant mice. Histograms present c mean onset (days) and d mean survival (days) of vehicle- or M30-treated G93A-SOD1 mice. Values are means ± SEM (n = 13–16 per group; *p < 0.05, ** p < 0.001 vs. control group; one-way ANOVA). e Overall neurological deficit scores vs. the age of animals. The total neurological deficits were determined from four independent tests (rotarod performance, postural reflex, screen grasping and tail suspension behavior), as described in Materials and Methods. Total score of 12 represent a complete loss of motor function. Values are means ± SEM (n = 13–16 per group). f Weight vs. the age of animals. Values are means ± SEM. (Reproduced from [79])

Fig. 5

A schematic representation of methods allowing local delivery of neurotrophic factors and cellular transplantations performed in ALS animal models and patients. a Represents the cisterna magna. b Refers to the CSF. c Concerns intraspinal treatment. d Indicates the spinal intrathecal space. e Pertains to the intramuscular space. Abbreviations; human mesenchymal stem cells (hMSCs), human neuronal progenitor cells (hNPCs), recombinant Adeno-associated virus (rAAV), lentivirus (LV), human neuronal stem cells (hNSCs), glial restricted precursors (GRP), tetanus toxin heavy chain (TTC), fusion protein of IGF-1 and TTC (IGF-1:TTC), fusion protein of GDNF and TTC (GDNF:TTC)